Abstract
Pyruvate kinase M2 (PKM2), a glycolytic enzyme, acts as a metabolic function leading to an energy production critical for cancer progression, known as Warburg effect. In this study we showed a pivotal role of PKM2 acting as a non-metabolic function to promote cancer cell progression in human oral squamous cell carcinoma (OSCC) through the induction of epithelial-mesenchymal transition (EMT), which is crucial for the potential in cancer cell invasion, and post-translational TGIF2 degradation. PKM2 immunoreaction was strong in the cytoplasm of invasive cancer cells, and distinct in the nucleus of spindle-shaped cancer cells with EMT characteristics. TGIF2 nuclear immunoreaction was seen in dysplastic epithelial cells but was repressed in cancer cells. In vitro analyses, cytoplasmic expression of PKM2 was translocated into the nucleus in human OSCC derived HSC-4 and SAS cells when EMT was stimulated. In addition, nuclear expression of TGIF2 was distinctively repressed in EMT induced HSC-4 and SAS cells. We recognized a mismatch in TGIF2 protein and mRNA expression in EMT induced HSC-4 and SAS cells and found that TGIF2 protein was post-translationally degraded through a ubiquitin proteasome system by an MG132 proteasome inhibition assay. Finally, promotion of HSC-4 and SAS cell progression by PKM2 was recognized in PKM2 knockdown assays. Thus, we clarified a new mechanism of non-metabolic function of PKM2 to promote the progression of OSCC through PKM2 nuclear translocation, subsequently induced EMT, and post-translationally repressed TGIF2 expression by a ubiquitin proteasome system.
Highlights
Oral cancers are the sixth most common cancers in the world [1]
In this study we showed a pivotal role of Pyruvate kinase M2 (PKM2) acting as a non-metabolic function to promote cancer cell progression in human oral squamous cell carcinoma (OSCC) through the induction of epithelial-mesenchymal transition (EMT), which is crucial for the potential in cancer cell invasion, and post-translational transforming growth factor β (TGF-β)-induced factor homeobox 2 (TGIF2) degradation
These PKM2 and TGIF2 were predominantly expressed in tumor cells, and this was confirmed by the following dual immunofluorescent staining against the same case shown in Figure 1A; g
Summary
Oral cancers are the sixth most common cancers in the world [1]. Oral squamous cell carcinoma (OSCC) accounts for more than 90% of oral cancers [2]. OSCC sometimes metastasizes to cervical lymph nodes. When metastasis occurs, it shows poor prognosis [3]. In tumor invasion and metastasis, epithelial-mesenchymal transition (EMT) plays an essential role [4, 5]. EMT has been primarily known as a phenotypic change during embryonic development, tissue remodeling and wound healing [6]. When EMT occurs, cells lose intercellular adhesion, alter morphology to spindle-shaped appearance, and increase mobility [6]
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